Project Summary Innate lymphoid cells (ILC) are recently discovered tissue-resident self-renewing immune cells with critical roles in barrier defense, tissue regeneration and immune regulation. Our preliminary data indicate that ILC gradually diminish in number with age. The goal of this project is to understand the cellular and molecular mechanisms that result in loss of ILC with age, and to examine whether diminished ILC numbers contribute to increased susceptibility to infections and diseases in the aged. This project focuses on group-2 innate lymphoid cells (ILC2), the predominant ILC subset in the lung. We hypothesize that decreased TCF-1 expression impairs ILC2 self-renewal and results in diminished numbers of ILC2 with age, and that diminished ILC2 responses contribute to increased susceptibility to influenza infection in the aged. We will use novel TCF- 1YFP and TCF-1 conditional knockout mice to explore the cellular and molecular mechanisms that control the longevity and self-renewal of lung-resident ILC2. We will determine whether dysregulation of such mechanisms results in loss of ILC2 with age. We will further use adoptive transfer approaches to examine whether and how diminished ILC2 responses contribute to increased susceptibility to influenza in aged mice. Finally, we will develop strategies to restore ILC2 numbers in the aged, and will test the efficacy of these strategies to enhance resistance to influenza in old mice. We anticipate that this work will provide significant insights into lymphocyte aging, and will inform strategies to improve immune defense in the elderly.